tbuckley/cabot-search huggingface dataset:
Magnetic Delivery of Antigen‐Loaded Magnetic Liposomes for Active Lymph Node Targeting and Enhanced Anti‐Tumor Immunity
Authors: Jingyi Sheng, Yang Liu, He Ding, Linyuan Wu, Lan Liu, Guangxiang Si, Yan Shen, Fang Yang, Ning Gu
Journal: Advanced Healthcare Materials (2023)

Therapeutic cancer vaccines offer the greatest advantage of enhancing antigen-specific immunity against tumors, particularly for immunogenic tumors, such as melanoma. However, clinical responses remain unsatisfactory, primarily due to inadequate T cell priming and the development of acquired immune tolerance. A major obstacle lies in the inefficient uptake of antigen by peripheral dendritic cells (DCs) and their migration to lymph nodes for antigen presentation. In this context, the magnetic delivery of antigen-loaded magnetic liposomes (Ag-MLs) to actively target lymph node, is proposed. These magnetic responsive liposomes contain soluble mouse melanoma lysate and iron oxide nanoparticles in the core, along with the immunostimulatory adjuvant CpG-1826 incorporated into the lipid bilayer. When applied through magnetic targeting in the mouse melanoma model, Ag-MLs accumulate significantly in the target lymph nodes. This accumulation results in increased population of active DCs in lymph nodes and cytotoxic T lymphocytes (CTLs) within tumors, correlating with effective tumor growth inhibition. Overall, this study demonstrates the potential of magnetic targeting as an effective strategy for delivering cancer vaccines and activating the immune response, offering a novel platform for cancer immunotherapies.
In Situ Insonation of Alkaline Buffer Containing Liposomes Leads to a Net Improvement of the Therapeutic Outcome in a Triple Negative Breast Cancer Murine Model
Authors: Deyssy Patrucco, Juan Carlos Cutrin, Dario Livio Longo, Elena Botto, Li Cong, Silvio Aime, Daniela Delli Castelli
Journal: Advanced Healthcare Materials (2023)

Breast cancer is characterized by an acidic micro-environment. Acidic extracellular pH gives cancer cells an evolutionary advantage, hence, neutralization of the extracellular pH has been considered as a potential therapeutic strategy. To address the issue of systemic pH alteration, an approach based on the targeted delivery of the buffering solution to the tumor region is investigated. The method relies on the use of low frequency ultrasound and sono-sensitive liposomes loaded with buffers at alkaline pH (LipHUS). After the i.v. injection of LipHUS, the application of ultrasound (US) at the sites of the pathology induces a local increase of pH that results highly effective in i) inhibiting primary tumor growth, ii) reducing tumor recurrence after surgery, and iii) suppressing metastases' formation. The experiments are carried out on a triple negative breast cancer mouse model. The results obtained demonstrate that localized and triggered release of bicarbonate or PBS buffer from sonosensitive liposomes represents an efficient therapeutic tool for treating triple-negative breast cancer. This approach holds promise for potential clinical translation.
Leveraging 3D Bioprinting and Photon‐Counting Computed Tomography to Enable Noninvasive Quantitative Tracking of Multifunctional Tissue Engineered Constructs
Authors: Carmen J. Gil, Connor J. Evans, Lan Li, Alex J. Allphin, Martin L. Tomov, Linqi Jin, Merlyn Vargas, Boeun Hwang, Jing Wang, Victor Putaturo, Gabriella Kabboul, Anjum S. Alam, Roshni K. Nandwani, Yuxiao Wu, Asif Sushmit, Travis Fulton, Ming Shen, Jarred M. Kaiser, Liqun Ning, Remi Veneziano, Nick Willet, Ge Wang, Hicham Drissi, Eric R. Weeks, Holly D. Bauser‐Heaton, Cristian T. Badea, Ryan K. Roeder, Vahid Serpooshan
Journal: Advanced Healthcare Materials (2023)

3D bioprinting is revolutionizing the fields of personalized and precision medicine by enabling the manufacturing of bioartificial implants that recapitulate the structural and functional characteristics of native tissues. However, the lack of quantitative and noninvasive techniques to longitudinally track the function of implants has hampered clinical applications of bioprinted scaffolds. In this study, multimaterial 3D bioprinting, engineered nanoparticles (NPs), and spectral photon-counting computed tomography (PCCT) technologies are integrated for the aim of developing a new precision medicine approach to custom-engineer scaffolds with traceability. Multiple CT-visible hydrogel-based bioinks, containing distinct molecular (iodine and gadolinium) and NP (iodine-loaded liposome, gold, methacrylated gold (AuMA), and Gd
Recruitment of a Middling Promiscuous Enzyme Drives Adaptive Metabolic Evolution in <i>Escherichia coli</i>
Authors: Ryan P Campbell, A Carl Whittington, Diego A R Zorio, Brian G Miller
Journal: Molecular Biology and Evolution (2023)

Abstract A key step in metabolic pathway evolution is the recruitment of promiscuous enzymes to perform new functions. Despite the recognition that promiscuity is widespread in biology, factors dictating the preferential recruitment of one promiscuous enzyme over other candidates are unknown. Escherichia coli contains four sugar kinases that are candidates for recruitment when the native glucokinase machinery is deleted—allokinase (AlsK), manno(fructo)kinase (Mak), N-acetylmannosamine kinase (NanK), and N-acetylglucosamine kinase (NagK). The catalytic efficiencies of these enzymes are 103- to 105-fold lower than native glucokinases, ranging from 2,400 M−1 s−1 for the most active candidate, NagK, to 15 M−1 s−1 for the least active candidate, AlsK. To investigate the relationship between catalytic activities of promiscuous enzymes and their recruitment, we performed adaptive evolution of a glucokinase-deficient E. coli strain to restore glycolytic metabolism. We observed preferential recruitment of NanK via a trajectory involving early mutations that facilitate glucose uptake and amplify nanK transcription, followed by nonsynonymous substitutions in NanK that enhance the enzyme's promiscuous glucokinase activity. These substitutions reduced the native activity of NanK and reduced organismal fitness during growth on an N-acetylated carbon source, indicating that enzyme recruitment comes at a cost for growth on other substrates. Notably, the two most active candidates, NagK and Mak, were not recruited, suggesting that catalytic activity alone does not dictate evolutionary outcomes. The results highlight our lack of knowledge regarding biological drivers of enzyme recruitment and emphasize the need for a systems-wide approach to identify factors facilitating or constraining this important adaptive process.
New Evolutionary Insights into RpoA: A Novel Quorum Sensing Reprograming Factor in <i>Pseudomonas aeruginosa</i>
Authors: Wenjie Cai, Huimin Liao, Mingqi Lu, Xiangting Zhou, Xiaoyan Cheng, Christian Staehelin, Weijun Dai
Journal: Molecular Biology and Evolution (2023)

Quorum-sensing (QS) coordinates the expression of virulence factors in Pseudomonas aeruginosa, an opportunistic pathogen known for causing severe infections in immunocompromised patients. QS has a master regulator, the lasR gene, but in clinical settings, P. aeruginosa isolates have been found that are QS-active but LasR-null. In this study, we developed an experimental evolutionary approach to identify additional QS-reprogramming determinants. We began the study with a LasR-null mutant with an extra copy of mexT, a transcriptional regulator gene that is known to be able to reprogram QS in laboratory LasR-null strains. In this strain, spontaneous single mexT mutations are expected to have no or little phenotypic consequences. Using this novel method, which we have named "targeted gene duplication followed by mutant screening", we identified QS-active revertants with mutations in genes other than mexT. One QS-active revertant had a point mutation in rpoA, a gene encoding the α-subunit of RNA polymerase. QS activation in this mutant was found to be associated with the downregulated expression of mexEF-oprN efflux pump genes. Our study therefore uncovers a new functional role for RpoA in regulating QS activity. Our results indicate that a RpoA-dependent regulatory circuit controlling the expression of the mexEF-oprN operon is critical for QS-reprogramming. In conclusion, our study reports on the identification of non-MexT proteins associated with QS-reprogramming in a laboratory strain, shedding light on possible QS activation mechanisms in clinical P. aeruginosa isolates.
Family Typology for Adults With Type 2 Diabetes: Longitudinal Stability and Validity for Diabetes Management and Well-being
Authors: Lindsay S. Mayberry, Shilin Zhao, McKenzie K. Roddy, Andrew J. Spieker, Cynthia A. Berg, Lyndsay A. Nelson, Robert A. Greevy
Journal: Diabetes Care (2023)

OBJECTIVE We validated longitudinally a typology of diabetes-specific family functioning (named Collaborative and Helpful, Satisfied with Low Involvement, Want More Involvement, and Critically Involved) in adults with type 2 diabetes. RESEARCH DESIGN AND METHODS We conducted k-means cluster analyses with nine dimensions to determine if the typology replicated in a diverse sample and if type assignment was robust to variations in sampling and included dimensions. In a subsample with repeated assessments over 9 months, we examined the stability and validity of the typology. We also applied a multinomial logistic regression approach to make the typology usable at the individual level, like a diagnostic tool. RESULTS Participants (N = 717) were 51% male, more than one-third reported minority race or ethnicity, mean age was 57 years, and mean hemoglobin A1c (HbA1c) was 7.9% (63 mmol/mol; 8.7% [72 mmol/mol] for the longitudinal subsample). The typology was replicated with respect to the number of types and dimension patterns. Type assignment was robust to sampling variations (97% consistent across simulations). Type had an average 52% stability over time within participants; instability was not explained by measurement error. Over 9 months, type was independently associated with HbA1c, diabetes self-efficacy, diabetes medication adherence, diabetes distress, and depressive symptoms (all P &amp;lt; 0.05). CONCLUSIONS The typology of diabetes-specific family functioning was replicated, and longitudinal analyses suggest type is more of a dynamic state than a stable trait. However, type varies with diabetes self-management and well-being over time as a consistent independent indicator of outcomes. The typology is ready to be applied to further precision medicine approaches to behavioral and psychosocial diabetes research and care.
Hydroxychloroquine in Stage 1 Type 1 Diabetes
Authors: Ingrid Libman, Polly J. Bingley, Dorothy Becker, Jane H. Buckner, Linda A. DiMeglio, Stephen E. Gitelman, Carla Greenbaum, Michael J. Haller, Heba M. Ismail, Jeffrey Krischer, Wayne V. Moore, Antoinette Moran, Andrew B. Muir, Vana Raman, Andrea K. Steck, Frederico G.S. Toledo, John Wentworth, Diane Wherrett, Perrin White, Lu You, Kevan C. Herold, Andrea K. Steck, Carla Greenbaum, Sandra Lord, Roshanak Monzavi, Lorraine Levitt Katz, Robin Goland, Andrew B. Muir, Elaine Apperson, Linda A. DiMeglio, Elizabeth Cummings, Ruth Weinstock, Jason Gaglia, Fiona Campbell, Susanne Cabrera, Samer Nakhle, Patrick English, Tony Huynh, David Liljenquist, Christopher Moudiotis, Sally-Anne Duke, Emanuele Bosi, Kurt Griffin, Henrik Borg, Ake Lernmark, Daniel Flynn, Darrell Wilson, Maria Craig, Wayne V. Moore, Diane Wherrett, Danijela Tatovich, Stephen E. Gitelman, Louis Philipson, Michael J. Haller, Mikael Knip, Eva Tsalikian, David Baidal, Inas Thomas, Antoinette Moran, Ingrid Libman, Perrin White, Vandana Raman, Zoe Raleigh, Christine Solorzano, Henry Rodriguez, William Russell, Michelle So, Peter Colman, Jennifer Couper, Jennifer Sherr
Journal: Diabetes Care (2023)

OBJECTIVE Innate immune responses may be involved in the earliest phases of type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS To test whether blocking innate immaune cells modulated progression of the disease, we randomly assigned 273 individuals with stage 1 T1D to treatment with hydroxychloroquine (n = 183; 5 mg/kg per day to a maximum of 400 mg) or placebo (n = 90) and assessed whether hydroxychloroquine treatment delayed or prevented progression to stage 2 T1D (i.e., two or more islet autoantibodies with abnormal glucose tolerance). RESULTS After a median follow-up of 23.3 months, the trial was stopped prematurely by the data safety monitoring board because of futility. There were no safety concerns in the hydroxychloroquine arm, including in annual ophthalmologic examinations. Preplanned secondary analyses showed a transient decrease in the glucose average area under the curve to oral glucose in the hydroxychloroquine-treated arm at month 6 and reduced titers of anti-GAD and anti-insulin autoantibodies and acquisition of positive autoantibodies in the hydroxychloroquine arm (P = 0.032). CONCLUSIONS We conclude that hydroxychloroquine does not delay progression to stage 2 T1D in individuals with stage 1 disease. Drug treatment reduces the acquisition of additional autoantibodies and the titers of autoantibodies to GAD and insulin.
Molecular Activation of NLRP3 Inflammasome by Particles and Crystals: A Continuing Challenge of Immunology and Toxicology
Authors: Qiang Ma, Chol Seung Lim
Journal: The Annual Review of Pharmacology and Toxicology (2023)

Particles and crystals constitute a unique class of toxic agents that humans are constantly exposed to both endogenously and from the environment. Deposition of particulates in the body is associated with a range of diseases and toxicity. The mechanism by which particulates cause disease remains poorly understood due to the lack of mechanistic insights into particle-biological interactions. Recent research has revealed that many particles and crystals activate the NLRP3 inflammasome, an intracellular pattern-recognition receptor. Activated NLRP3 forms a supramolecular complex with an adaptor protein to activate caspase 1, which in turn activates IL-1β and IL-18 to instigate inflammation. Genetic ablation and pharmacological inhibition of the NLRP3 inflammasome dampen inflammatory responses to particulates. Nonetheless, how particulates activate NLRP3 remains a challenging question. From this perspective, we discuss our current understanding of and progress on revealing the function and mode of action of the NLRP3 inflammasome in mediating adaptive and pathologic responses to particulates in health and disease.
Orexin Receptor Antagonism: Normalizing Sleep Architecture in Old Age and Disease
Authors: Jarrah O.-Z.J. Kron, Ryan J. Keenan, Daniel Hoyer, Laura H. Jacobson
Journal: The Annual Review of Pharmacology and Toxicology (2023)

Sleep is essential for human well-being, yet the quality and quantity of sleep reduce as age advances. Older persons (>65 years old) are more at risk of disorders accompanied and/or exacerbated by poor sleep. Furthermore, evidence supports a bidirectional relationship between disrupted sleep and Alzheimer's disease (AD) or related dementias. Orexin/hypocretin neuropeptides stabilize wakefulness, and several orexin receptor antagonists (ORAs) are approved for the treatment of insomnia in adults. Dysregulation of the orexin system occurs in aging and AD, positioning ORAs as advantageous for these populations. Indeed, several clinical studies indicate that ORAs are efficacious hypnotics in older persons and dementia patients and, as in adults, are generally well tolerated. ORAs are likely to be more effective when administered early in sleep/wake dysregulation to reestablish good sleep/wake-related behaviors and reduce the accumulation of dementia-associated proteinopathic substrates. Improving sleep in aging and dementia represents a tremendous opportunity to benefit patients, caregivers, and health systems.
Translational In Vivo Assays in Behavioral Biology
Authors: Sarah L. Withey, Diego A. Pizzagalli, Jack Bergman
Journal: The Annual Review of Pharmacology and Toxicology (2023)

The failure of preclinical research to advance successful candidate medications in psychiatry has created a paradigmatic crisis in psychiatry. The Research Domain Criteria (RDoC) initiative was designed to remedy this situation with a neuroscience-based approach that employs multimodal and cross-species in vivo methodology to increase the probability of translational findings and, consequently, drug discovery. The present review underscores the feasibility of this methodological approach by briefly reviewing, first, the use of multidimensional and cross-species methodologies in traditional behavioral pharmacology and, subsequently, the utility of this approach in contemporary neuroimaging and electrophysiology research—with a focus on the value of functionally homologous studies in nonhuman and human subjects. The final section provides a brief review of the RDoC, with a focus on the potential strengths and weaknesses of its domain-based underpinnings. Optimistically, this mechanistic and multidimensional approach in neuropsychiatric research will lead to novel therapeutics for the management of neuropsychiatric disorders. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 64 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
IL-33 Expression Is Lower in Current Smokers at both Transcriptomic and Protein Levels
Authors: Alen Faiz, Rashad M. Mahbub, Fia Sabrina Boedijono, Milan I. Tomassen, Wierd Kooistra, Wim Timens, Martijn Nawijn, Philip M. Hansbro, Matt D. Johansen, Simon D. Pouwels, Irene H. Heijink, Florian Massip, Maria Stella de Biase, Roland F. Schwarz, Ian M. Adcock, Kian F. Chung, Anne van der Does, Pieter S. Hiemstra, Helene Goulaouic, Heming Xing, Raolat Abdulai, Emanuele de Rinaldis, Danen Cunoosamy, Sivan Harel, David Lederer, Michael C. Nivens, Peter A. Wark, Huib A. M. Kerstjens, Machteld N. Hylkema, Corry-Anke Brandsma, Maarten van den Berge
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

IL-33 is a proinflammatory cytokine thought to play a role in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). A recent clinical trial using an anti-IL-33 antibody showed a reduction in exacerbation and improved lung function in ex-smokers but not current smokers with COPD.
Post-Traumatic Pulmonary Hematoma Presenting as Multiple Ring-shaped Spherical Nodules
Authors: Orito Ikeda, Kunihiko Shimizu, Yoshitake Yamada, Hiroaki Sugiura, Miki Takahashi, Tokuhiro Kimura, Hideaki Suzuki, Kozo Sato, Masahiro Jinzaki
Journal: American Journal of Respiratory and Critical Care Medicine (2023)
A translational perspective towards clinical AI fairness
Authors: Mingxuan Liu, Yilin Ning, Salinelat Teixayavong, Mayli Mertens, Jie Xu, Daniel Shu Wei Ting, Lionel Tim-Ee Cheng, Jasmine Chiat Ling Ong, Zhen Ling Teo, Ting Fang Tan, Narrendar RaviChandran, Fei Wang, Leo Anthony Celi, Marcus Eng Hock Ong, Nan Liu
Journal: npj Digital Medicine (2023)

Abstract Artificial intelligence (AI) has demonstrated the ability to extract insights from data, but the fairness of such data-driven insights remains a concern in high-stakes fields. Despite extensive developments, issues of AI fairness in clinical contexts have not been adequately addressed. A fair model is normally expected to perform equally across subgroups defined by sensitive variables (e.g., age, gender/sex, race/ethnicity, socio-economic status, etc.). Various fairness measurements have been developed to detect differences between subgroups as evidence of bias, and bias mitigation methods are designed to reduce the differences detected. This perspective of fairness, however, is misaligned with some key considerations in clinical contexts. The set of sensitive variables used in healthcare applications must be carefully examined for relevance and justified by clear clinical motivations. In addition, clinical AI fairness should closely investigate the ethical implications of fairness measurements (e.g., potential conflicts between group- and individual-level fairness) to select suitable and objective metrics. Generally defining AI fairness as “equality” is not necessarily reasonable in clinical settings, as differences may have clinical justifications and do not indicate biases. Instead, “equity” would be an appropriate objective of clinical AI fairness. Moreover, clinical feedback is essential to developing fair and well-performing AI models, and efforts should be made to actively involve clinicians in the process. The adaptation of AI fairness towards healthcare is not self-evident due to misalignments between technical developments and clinical considerations. Multidisciplinary collaboration between AI researchers, clinicians, and ethicists is necessary to bridge the gap and translate AI fairness into real-life benefits.
A randomized trial of a mobile health intervention to augment cardiac rehabilitation
Authors: Jessica R. Golbus, Kashvi Gupta, Rachel Stevens, V.Swetha E. Jeganathan, Evan Luff, Jieru Shi, Walter Dempsey, Thomas Boyden, Bhramar Mukherjee, Sarah Kohnstamm, Vlad Taralunga, Vik Kheterpal, Susan Murphy, Predrag Klasnja, Sachin Kheterpal, Brahmajee K. Nallamothu
Journal: npj Digital Medicine (2023)

Abstract Mobile health (mHealth) interventions may enhance positive health behaviors, but randomized trials evaluating their efficacy are uncommon. Our goal was to determine if a mHealth intervention augmented and extended benefits of center-based cardiac rehabilitation (CR) for physical activity levels at 6-months. We delivered a randomized clinical trial to low and moderate risk patients with a compatible smartphone enrolled in CR at two health systems. All participants received a compatible smartwatch and usual CR care. Intervention participants received a mHealth intervention that included a just-in-time-adaptive intervention (JITAI) as text messages. The primary outcome was change in remote 6-minute walk distance at 6-months stratified by device type. Here we report the results for 220 participants enrolled in the study (mean [SD]: age 59.6 [10.6] years; 67 [30.5%] women). For our primary outcome at 6 months, there is no significant difference in the change in 6 min walk distance across smartwatch types (Intervention versus control: +31.1 meters Apple Watch, −7.4 meters Fitbit; p = 0.28). Secondary outcomes show no difference in mean step counts between the first and final weeks of the study, but a change in 6 min walk distance at 3 months for Fitbit users. Amongst patients enrolled in center-based CR, a mHealth intervention did not improve 6-month outcomes but suggested differences at 3 months in some users.
Tumors recycle glucocorticoids to drive Treg-mediated immunosuppression
Authors: Julian Swatler, Young-Jun Ju, Ana C. Anderson, Enrico Lugli
Journal: Journal of Clinical Investigation (2023)

Suppression of antitumor immunity is a prominent feature of the tumor microenvironment. In this issue of the JCI, Taves, Otsuka, and authors show that glucocorticoids (GCs), which are potent immunosuppressive hormones mainly produced by the adrenals, can be reconverted from their inactive form to active metabolites via the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme expressed by murine tumor cell lines. In the tumor microenvironment, GCs acted on CD4+ regulatory T cells to enhance their immunosuppressive function and promote tumor growth. The findings suggest that targeting GC recycling as a strategy for modulating tumor immunosuppression has the potential to improve therapeutic efficacy of immune checkpoint blockade.